The treatment of diseases of the brain is significantly limited by the blood brain barrier. Over the last decade intranasal administration of drugs has gained increasing interest as a non-parenteral therapy. Originally seen as a route of administration for the local treatment of congestion, infection, rhinitis or nasal polyposis, in recent years a variety of products have entered the market for the systemic treatment of a variety of ailments. Nasal delivery of drugs has many advantages, including avoidance of first pass metabolism and degradation in the gut, rapid onset with quick diffusion into the systemic system that parallels with intravenous administration and patient compliance due to the non-invasive nature and ease of self-medication.
Within the nasal passage there are two main areas of absorption: the respiratory zone, which has the largest surface area and is highly vascularised, where active principles can cross the epithelium via para-or-transcellular routes, and the olfactory epithelium. The latter comprises only 3-5% of the total surface area of the nasal cavity and therefore is not largely involved in systemic absorption, but can allow direct access to the CNS, bypassing the blood brain barrier via the processes of olfactory neurons, through to the synaptic junctions with neurons of the olfactory bulb.
There are physical disadvantages associated with administration via the nasal route that must be overcome. These include mucociliary clearance, enzymatic activity of the nasal mucosa, peptidases and drug metabolising enzymes. In addition, molecular weight and lipophilicity play a part in absorption—low molecular weight molecules having a molecular weight less than 300 Da tend to be rapidly absorbed whereas for molecules between 300-1000 Da, liposolubility is an important property. Lipophilic molecules diffuse freely, whereas it is thought that hydrophilic molecules must pass through the paracellular route. Molecules with a molecular weight above 1 kDa absorb very slowly and have a low bioavailability. These barriers can be addressed by altering the physiochemical properties of the molecule, increasing permeability by coadministration of an absorption promoter or reducing excretion/degradation by co-administering inhibitors. Absorption promoters currently under development include alkylsaccharides (Intravail®), chitosan (ChiSys™), low methylated pectin (PecSys™) and polyethylene glycol (30%).
Chitosan and its derivatives are commonly used as absorption enhancers due to chisosan's well documented ability to facilitate paracellular transport by opening the tight junctions or by interacting with extra-cellular matrix components. Chitosan increases the bioavailability of verapamil when administered nasally to rabbits in comparison to nasal verapamil solution (Abdel Mouez et al; Eur J Pharm Sci 2013, 30, 59-66). In addition, polylactic acid nanoparticles modified with chitosan have been used to encapsulate the analgesic peptide Neurotoxin. Rats intranasally administered with these chitosan modified nanoparticles had an increased concentration of neurotoxin in the periaqueductal gray in comparison to polylactic acid alone loaded nanoparticles (Zhang et al; Drug Development and Industrial Pharmacy 2013, 39, (11), 1618-24).
Endogenous opioid peptides Leucine5-enkephalin (LENK) and Methionine5-enkephalin (MENK) are mainly degraded by cleavage of the N-terminal tyrosine. In the presence of polycarbophil-cysteine (0.25%) and glutathione (1%) LENK has shown reduced degradation and enhanced transportation across freshly excised bovine nasal mucosa. The absorption enhancer sodium glycocholate and protease inhibiter puromycin co-administered with LENK reduced degradation in nasal washings. However this combination of excipients can lead to cell leakage and therefore toxicity.
Chitosan formulations can also reduce the degradation of peptides. For instance, a chitosan-EDTA conjugate has been shown to reduce the degradation of LENK (Bernkop-Schnürch et al; 1997, Pharm Res 14, 917-22). LENK has also been nasally administered with trimethyl chitosan nanoparticles and shown enhanced antinociception in two mouse pain models in comparison to LENK alone (Kumar et al; Int J Biol Macromol 2013, 61C, 189-195).
WO2004/026912 describes polysaccharides which are used to solubilise hydrophobic drugs. The polysaccharides are amphiphilic and are generally selected from any derivatives of the following: chitosans, dextrans, alginic acids, starches, dextran and guar gums. Quaternary ammonium palmitoyl glycol chitosan (GCPQ) and quaternary ammonium hexadecyl glycol chitosan (GCHQ) are used in the Examples of this patent application as solubilising polysaccharides.
WO2008/017839 describes micellar clusters formed from amphiphilic carbohydrate polymers and their use in formulating hydrophobic drugs. GCPQ is specifically exemplified as an amphiphilic carbohydrate polymer.
In U.S. Pat. No. 8,278,277 a lipid ester prodrug of LENK is formed and added to a composition comprising GCPQ. The compositions are delivered intravenously or orally. The prodrug was converted to LENK in vivo and shown to result in significant LENK brain levels. However, none of these prior art patent publications discuss formulations involving hydrophilic drugs per se.